Congestive Heart Failure
Heart failure currently affects more than two million Americans and its economic and human toll will continue to increase as the population ages. Congestive heart failure is the most common inpatient diagnosis for patients 65 years old and older, [Funk, 1996 #14], with more than 400,000 new cases reported each year [Cohn, 1991 #15]. The prognosis is poor, with 60% mortality within 5 years [Cohn, 1991 #15], and 23–52% of deaths attributable to fatal arrhythmias (sudden cardiac death; SCD) [Investigators, 1992 #17; Cohn, 1991 #15].
Heart failure is an inability to match cardiac output to physiological demand. Heart failure is therefore not a specific disease, but a syndrome that represents the end-point of most cardiac diseases, including ischemic heart disease, cardiomyopathies (dilative, restrictive, or hypertrophic), valvular heart diseases and long term hypertension and diabetes. In addition, the symptoms of heart failure can also present acutely (i.e. acute heart failure, or cardiogenic shock) in instances as acute myocardial infarction, post cardiac surgery (stunning, hybernation) or post re-vascularization therapy (i.e. reperfusion injury, post thrombolysis, percutaneous transluminal coronary angioplasty or coronary artery by-pass grafting).
Heart Failure and Cellular Excitation-Contraction Coupling
A momentous discovery was made in the early 1990s, when it was demonstrated that heart failure is ultimately due to changes at the level of the heart cells, which are unable to develop sufficient contractile force. At a cellular level, cardiac contractile force depends on the amplitude of the transient rise in calcium during the action potential (i.e. the Cai transients). The chain of events that link membrane depolarization during the action potential to the Cai transient is called excitation-contraction coupling (ECC). Central to the current model of ECC in heart lies the process of Ca-induced Ca-release (CICR) [Fabiato, 1983 #26]. During the action potential, membrane depolarization opens sarcolemmal Ca channels and allows Ca entry into the cell (which can be measured as L-type Ca current, ICa,L). Sarcolemmal L-type Ca channels are in close apposition to the intracellular release channels of the sarcoplasmic reticulum (SR, the internal Ca stores), also known as ryanodine receptors (RyR). Entry through L-type Ca channels triggers the opening of the RyR, followed by a large efflux of Ca from the SR into the cytosol. The rise in cytosolic Cai activates the actin-myosin interaction. The subsequent cell shortening and force development will thus depend on both the Cai transient amplitude and the myolilament sensitivity for Ca. In turn, the amplitude of the Cai transients will depend on the amplitude of the trigger ICa,L as well as the amount of Ca stored in the SR (the SR Ca load, CaSR).
In diastole, heart relaxation is brought about by Ca2+ removal from cytoplasm, mainly by two mechanisms: about 70% of Ca2+ is taken up into the SR though the action of the SR Ca pump, and is made available for next Ca release episode. The remainder 30% of cytosolic Ca is extruded from the cell by the sarcolemmal sodium/calcium exchanger (NCX).
In failing heart cells, the ECC process is corrupted, and cytosolic Ca2+ ([Ca2+]i) does not rise sufficiently during the action potential to activate the required myofilament force [Gwathmey, 1987 #109]. A typical failing heart cell shows a decrease in the ability of the internal stores (the SR) to load with Ca2+,due to a downregulation of SERCA [O'Rourke, 1999 #46]. Another component of altered Ca2+ handling in both human disease [Studer, 1994 #79] and animal models [Hobai, 2000 #37; Pogwizd, 1999 #42] is an increase in Ca2+ extrusion from the cell by the NCX due to NCX overexpression. However, it has been previously unclear whether NCX overexpression is compensatory or one of the primary deficits. One widely held theory has been that NCX overexpression compensated for decreased Ca2+ re-uptake into the SR in diastole by increasing Ca2+ extrusion from the cell [Hasenfuss. 1999 #91], which improved relaxation (positive lusitropic), but at the cost of a further depletion of SR Ca2+ stores (negative inotropic). Further complicating the issue was the observation that NCX overexpression has also been found in hypercontractile models with no SR dysfunction [Sipido, 2000 #36].
Approved and Experimental Treatment Strategies
Despite continuous improvements, the treatment of heart failure is at this time unsatisfactory. Although the foundation of this disease is represented by the decrease in cardiac contractility, only two classes of drugs are approved for use to increase cardiac force (i.e. positive inotropes), cardiac glycosides (like digoxin) and beta-adrenergic agonists (like dobutamine, amrinone or milrinone). Importantly, despite an effective relief of symptoms, the use of these agents has been associated with no change (digoxin) or an increase (beta-adrenergic agonists) in mortality.
Other classes of agents used in heart failure exert their beneficial effects by preventing the long term cardiac remodeling (angiotensin convertin enzyme inhibitors, like captopril, and beta adrenergic blockers, like carvedilol) or by interfering with renal and vascular contributory mechanisms (like diuretics and nitrates). The long term beneficial effect of beta blockers is evident only after an initial, transient decrease in cardiac inotropy, with negative effects on both physician confidence and patient compliance. The need for new, effective positive inotropic drugs is, therefore, hard to overemphasize.
Numerous experimental therapeutic strategies have been or are currently evaluated.
Gene therapy strategies include altering the ratio of SERCA2a and phospholamban in the heart (pending patent to Rosenzweig, Hajjar, Guerrero, Luis; entitled “Use of agents to treat heart disorders”; Ser. No.: 789894; filed Feb. 21, 2001).